Although study methodologies have been intensely debated, a consensus has recently emerged that Alzheimer's disease (AD) is more likely to develop in women than in men. This gender-based difference has focused research on estrogen, and specifically, the lack of estrogen during aging in women as a contributing factor to the neuropathology of Alzheimer's disease. Estrogen is known to be beneficial to the CNS at many levels including direct effects on neurons. However, estrogen can also modify microglia activation and suppressing inflammation. Neurodegenerative diseases like Alzheimer's disease feature brain inflammation as a major component of the disease process. The brain's own macrophage, the microglia, participate in this chronic inflammatory response by releasing cytoactive factors such as reactive oxygen species (ROS), cytokines and proteases. Our previously published data demonstrate that the level of macrophage immune responsiveness is dependent on APOE genotype such that a higher level of activation was observed in human Alzheimer's disease patients expressing an APOE4 gene compared to Alzheimer's disease patients that do not express an APOE4 gene. The APOE 4 gene is a well-known "risk" factor for Alzheimer's disease and the observed increase in immune activation is consistent with the increased severity of neurodegeneration associated with APOE4 in Alzheimer's disease. The same pattern of enhanced macrophage activation is observed in mouse models that express human APOE 4 compared to those expressing human APOE3. Importantly, a gender differenced is observed in the APOE-mediated regulation of immune function suggesting that the presence of estrogen overrides the regulatory effects of the APOE4 gene. Our overarching goal of this research program is to understand brain inflammation in disease in the context of factors such as APOE genotype and gender that regulate the sensitivity of the immune system's responsiveness. Thus, we will examine the role of hormones in the regulation of microglial and peritoneal macrophage immune activation in mice expressing only human apoE3 protein or expressing only human apoE4 protein.